Pyrazofurin is a C-nucleoside antibiotic, 4-hydroxy-3-.beta.-D-ribofuranosylpyrazole-5-carboxamide, obtained initially by fermentation of a strain of Streptomyces candidus. In accordance with the nomenclature of the United States Adopted Names Council, pyrazofurin is the generic name which replaces the former generic name pyrazomycin. Methods for the production, recovery, purification, and characterization of pyrazofurin are described in detail in U.S. Pat. Nos. 3,674,774 and 3,802,999. Pyrazofurin has been shown to possess antiviral activity, for example against rhinovirus, measles, herpes simplex, and vaccinia viruses. In addition, pyrazofurin has exhibited antitumor activity against several carcinomas, as demonstrated by Sweeney, el al., Cancer Research, 33, 2619-2623 (1973).
Extensive research has been directed to the study of antiviral agents and to potential antitumor agents in general. Difficulty has generally been encountered in the development of antiviral agents because viruses are intracellular parasites which rely on the metabolic processes of the invaded call for their own existence. Consequently, agents which inhibit or kill the viruses may in addition injure the host cells that harbor them. Similarly, the severe systemic toxicity of many potentially useful antitumor agents generally limits their use.
Azauridine is one such antitumor agent which has been used successfully to produce partial remissions of acute leukemias in adults; however, the results obtained are generally only temporary. Large intravenous doses are required because of its poor absorption from the intestine, and sustained blood levels are difficult to maintain due to its rapid excretion. An orally effective triacetyl derivative of azauridine, Azaribine.RTM., has been prepared in an effort to increase effective blood levels of free azauridine. However, moderate anemia and neurological disturbances are common side effects accompanying triacetylazauridine usage.
Considerable interest has recently been directed to pyrazofurin, not only because of its antiviral and antitumor activities, but also because it is one of very few C-nucleosides showing antitumor activity. The complete chemical synthesis of pyrazofurin has recently been reported by Farkas Flegelova, and Sorm, Tetrahedron Letters, 2279-2280 (1972). Panzica and Townsend have prepared several nucleosides which are structurally similar to pyrazofurin and which also display antitumor activity, Journal of Organic Chemistry, 36, 1594-1596 (1971).
It is an object of the present invention to provide novel C-nucleosides which are useful pharmacological agents. In particular, it is an object of this invention to provide certain acylated derivatives of pyrazofurin. Additionally, because normal acylation conditions when applied to pyrazofurin lead to very complex mixtures of partial and total acylates, it is a further object of this invention to provide processes whereby various partial acylates of pyrazofurin are cleanly prepared. A still further object of this invention is to provide new compounds which display antiviral, antifungal, and antitumor activity, and are additionally useful as antipsoriatic agents.